Pyrazinoisoquinoline compounds

ABSTRACT

This invention in one embodiment is directed to a compound of Formula Ia; 
     
       
         
         
             
             
         
       
     
     where the designation (R) indicates that the designated carbon has the (R) stereochemistry; and wherein Z 1  is hydrogen or fluorine; Z 2  is hydrogen, deuterium, or fluorine; Z 3  is deuterium; Z 4  is fluorine; m is an integer from 0 to 10; n is an integer from 0 to 2; provided that: the sum of m+n does not exceed 10; and when both Z 1  and Z 2  are hydrogen, the sum of m+n is greater than 0, and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising one or more compounds of this invention and a carrier and the use of the disclosed compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering an antihelminthic agent, such as praziquantel.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 13/256,787, filed Sep. 15, 2011, which claims the benefit ofInternational Application No. PCT/2010/027476, filed Mar. 16, 2010,which claims the benefit of U.S. Provisional Patent Application No.61/210,279, filed Mar. 17, 2009. This application also claims thebenefit of U.S. Provisional Patent Application No. 61/449,312, filedMar. 4, 2011 and U.S. Provisional Patent Application No. 61/599,147,filed Feb. 15, 2012. The contents of the foregoing applications are eachincorporated herein by reference.

BACKGROUND OF THE INVENTION

Many current medicines suffer from poor absorption, distribution,metabolism and/or excretion (ADME) properties that prevent their Wideruse or limit their use in certain indications. Poor ADME properties arealso a major reason for the failure of drug candidates in clinicaltrials. While formulation technologies and prodrug strategies can beemployed in some cases to improve certain ADME properties, theseapproaches often fail to address the underlying ADME problems that existfor many drugs and drug candidates. One such problem is rapid metabolismthat causes a number of drugs, which otherwise would be highly effectivein treating a disease, to be cleared too rapidly from the body. Apossible solution to rapid drug clearance is frequent or high dosing toattain a sufficiently high plasma level of drug. This, however,introduces a number of potential treatment problems such as poor patientcompliance with the dosing regimen, side effects that become more acutewith higher doses, and increased cost of treatment. A rapidlymetabolized drug may also expose patients to undesirable toxic orreactive metabolites.

Another ADME limitation that affects many medicines is the formation oftoxic or biologically reactive metabolites. As a result, some patientsreceiving the drug may experience toxicities, or the safe dosing of suchdrugs may be limited such that patients receive a suboptimal amount ofthe active agent. In certain cases, modifying dosing intervals orformulation approaches can help to reduce clinical adverse effects, butoften the formation of such undesirable metabolites is intrinsic to themetabolism of the compound.

In some select cases, a metabolic inhibitor will be co-administered witha drug that is cleared too rapidly. Such is the case with the proteaseinhibitor class of drugs that are used to treat HIV infection. The FDArecommends that these drugs be co-dosed with ritonavir, an inhibitor ofcytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsiblefor their metabolism (see Kempf, D. J. et al., Antimicrobial agents andchemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverseeffects and adds to the pill burden for HIV patients who must alreadytake a combination of different drugs. Similarly, the CYP2D6 inhibitorquinidine has been added to dextromethorphan for the purpose of reducingrapid CYP2D6 metabolism of dextromethorphan in a treatment ofpseudobulbar affect. Quinidine, however, has unwanted side effects thatgreatly limit its use in potential combination therapy (see Wang, L etal., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67;and FDA label for quinidine at www.accessdata.fda.gov).

In general, combining drugs with cytochrome P450 inhibitors is not asatisfactory strategy for decreasing drug clearance. The inhibition of aCYP enzyme's activity can affect the metabolism and clearance of otherdrugs metabolized by that same enzyme. CYP inhibition can cause otherdrugs to accumulate in the body to toxic levels.

A potentially attractive strategy for improving a drug's metabolicproperties is deuterium modification. In this approach, one attempts toslow the CYP-mediated metabolism of a drug or to reduce the formation ofundesirable metabolites by replacing one or more hydrogen atoms withdeuterium atoms. Deuterium is a safe, stable, non-radioactive isotope ofhydrogen. Compared to hydrogen, deuterium forms stronger bonds withcarbon. In select cases, the increased bond strength imparted bydeuterium can positively impact the ADME properties of a drug, creatingthe potential for improved drug efficacy, safety, and/or tolerability.At the same time, because the size and shape of deuterium areessentially identical to those of hydrogen, replacement of hydrogen bydeuterium would not be expected to affect the biochemical potency andselectivity of the drug as compared to the original chemical entity thatcontains only hydrogen.

Over the past 35 years, the effects of deuterium substitution on therate of metabolism have been reported for a very small percentage ofapproved drugs (see, e.g., Blake, M I et al, J Pharm Sci, 1975,64:367-91; Foster, AB, Adv Drug Res 1985, 14:1-40 (“Foster”); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, M B et al, CurrOpin Drug Discov Devel, 2006, 9:101-09 (“Fisher”)). The results havebeen variable and unpredictable. For some compounds deuteration causeddecreased metabolic clearance in vivo. For others, there was no changein metabolism. Still others demonstrated increased metabolic clearance.The variability in deuterium effects has also led experts to question ordismiss deuterium modification as a viable drug design strategy forinhibiting adverse metabolism (see Foster at p. 35 and Fisher at p.101).

The effects of deuterium modification on a drug's metabolic propertiesare not predictable even when deuterium atoms are incorporated at knownsites of metabolism. Only by actually preparing and testing a deuterateddrug can one determine if and how the rate of metabolism will differfrom that of its non-deuterated counterpart. See, for example, Fukuto etal. (J. Med. Chem. 1991, 34, 2871-76). Many drugs have multiple siteswhere metabolism is possible. The site(s) where deuterium substitutionis required and the extent of deuteration necessary to see an effect onmetabolism, if any, will be different for each drug.

Praziquantel, also known as2-(cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one,acts as an antihelminthic agent through mechanisms as yet unproven,although experimental evidence indicates that praziquantel increases thepermeability of parasitic cell membranes to calcium ions, therebyinducing contraction of the parasites. The drug, sold as Biltricide,further causes vacuolization and disintegration of the parasitetegument. (See FDA label for BILTRICIDE® athttp://www.fda.gov/cder/foi/label/2004/18714s008,009lbl.pdf) (lastvisited Feb. 20, 2009)).

Praziquantel is currently approved for the treatment of infections dueto all species of schistosoma (e.g. Schistosoma mekongi, Schistosomajaponicum, Schistosoma mansoni and Schistosoma hematobium)—see, e.g.,The Lancet, Volume 376, Issue 974, Pages 496-498, 14 Aug. 2010.—andinfections due to the liver flukes, Clonorchis sinensis/Opisthorchisviverrini and is currently in clinical trials for the treatment ofcysticercosis, neurocysticercosis (NCC), and malaria. Praziquantel isalso useful for the treatment of indications that may be treated withanthelmintics, antischistosomals and antitrematodes, according tohttp://www.who.int/selection_medicines/committees/expert/17/sixteenth_adult_list_en.pdf(accessed February 2011). Praziquantel is also useful for the treatmentof fascioliasis, paragonimiasis, tapeworms and cestodes, including:Echinococcosis; Cysticercosis, though it has been judged less effectivethan albendazole in treatment of neurocysticercosis; and intestinaltapeworms, according to http://en.wikipedia.org/wiki/Praziquantel(accessed February 2011). According tohttp://www.drsfostersmith.com/Rx_Info_Sheets/rx_praziquantel.pdf,praziquantel is also useful in veterinary medicine, for example in dogsfor the removal of tapeworm. It is also useful in dogs in combinationwith pyrantel pamoate and febantel for the removal of hookwonns,roundworms, and whipworms. As another example, praziquantel is useful incats for the removal of tapeworm, and in combination with pyrantelpamoate also for the removal of various types of hookworms androundworms. As another example, praziquantel is useful in ferrets,birds, chinchillas, mice, rats, hamsters, gerbils, and guinea pigs forthe removal of tapeworms. As another example, praziquantel is useful inreptiles for the removal of tapeworms and flukes. A product containingpraziquantel and pyrantel pamoate is Drontal®, which, according tohttp://www.drugs.com/vet/drontal-praziquantel-pyrantel-pamoate-tablets.htmlwill remove tapeworms (Dipylidium caninum, Taenia taeniaeformis),hookworms (Ancylostoma tubaeforme), and large roundworms (Toxocara cati)in cats and kittens.

According to Meyer T, et al. (2009) “Taste, A New Incentive to Switch to(R-Praziquantel in Schistosomiasis Treatment.” PLoS Negl Trop Dis 3(1):e357. doi:10.1371/journal.pntd.0000357, the enantiomer of praziquantelhaving the (R) configuration is the enantiomer that has schistosomicidalactivity. The (R) enantiomer has the additional advantage of having asignificantly less bitter taste than racemic praziquantel.

Approximately 80% of a dose of praziquantel is excreted in the kidneys,almost exclusively (>99%) in the form of metabolites. (See FDA label forBILTRICIDE® @http://www.fda.gov/cder/foi/label/2004/18714s008,009lbl.pdf). The mainmetabolic pathway in humans involves CYP 2B1 and CYP 3A4 mediatedhydroxylation of praziquantel to the active (in vitro) metabolite,4′-hydroxypraziquantel (as a mixture of cis and trans). Because4′-hydroxypraziquantel is poorly taken-up by parasites in animal models,it is unlikely to contribute to efficacy in vivo. Additional metabolitesinclude CYP mediated hydroxylation of the parent to8-hydroxypraziquantel, and other unidentified mono- and di-hydroxylatedforms of the parent drug (Godawska-Matysik, A et al., Acta Pol Pharm,2006 September-October, 63(5):381-5).

Adverse events due to treatment with praziquantel are usually mild andtransient and do not require treatment. These effects include thefollowing, generally listed in order of severity: malaise, headache,dizziness, abdominal discomfort with or without nausea, rise intemperature and, rarely, urticaria. Such symptoms may also result fromthe infection itself and may be more frequent and/or serious in patientswith a heavy worm burden. Due to drug-drug interactions, recommendationsexist for co-dosing various drugs with praziquantel. Concomitantadministration of drugs that increase the activity of drug metabolizingliver enzymes (Cytochrome P450), e.g. antiepileptic drugs (phenyloin,phenobarbital and carbamazepine), dexamethasone, may reduce plasmalevels of praziquantel. Concomitant administration of rifampin should beavoided. Concomitant administration of drugs that decrease the activityof drug metabolizing liver enzymes (Cytochrome P 450), e.g. cimetidine,ketoconazole, itraconazole, erythromycin may increase plasma levels ofpraziquantel. Chloroquine, when taken simultaneously, may lead to lowerconcentrations of praziquantel in blood. The mechanism of this drug-druginteraction is unclear. (seehttp://www.fda.gov/cder/foi/label/2004/18714s008,009lbl.pda (lastvisited Feb. 20, 2009))

Despite the beneficial activities of Praziquantel, there is a continuingneed for new compounds to treat the aforementioned diseases andconditions.

SUMMARY OF THE INVENTION

This invention relates to novel compounds that are pyrazinoisoquinolinederivatives, and pharmaceutically acceptable salts thereof. Morespecifically, this invention relates to novel pyrazinoisoquinolinederivatives that are derivatives of praziquantel. This invention alsoprovides compositions comprising one or more compounds of this inventionand a carrier and the use of the disclosed compounds and compositions inmethods of treating diseases and conditions that are beneficiallytreated by administering an antihelminthic agent, such as praziquantel.

DETAILED DESCRIPTION OF THE INVENTION

The terms “ameliorate” and “treat” are used interchangeably and includeboth therapeutic treatment and prophylactic treatment (reducing thelikelihood of development). Both terms mean decrease, suppress,attenuate, diminish, arrest, or stabilize the development or progressionof a disease (e.g., a disease or disorder delineated herein), lessen theseverity of the disease or improve the symptoms associated with thedisease.

“Disease” means any condition or disorder that damages or interfereswith the normal function of a cell, tissue, or organ.

It will be recognized that some variation of natural isotopic abundanceoccurs in a synthesized compound depending upon the origin of chemicalmaterials used in the synthesis. Thus, a preparation of praziquantelwill inherently contain small amounts of deuterated isotopologues. Theconcentration of naturally abundant stable hydrogen and carbon isotopes,notwithstanding this variation, is small and immaterial as compared tothe degree of stable isotopic substitution of compounds of thisinvention. See, for instance, Wada E et al., Seikagaku 1994, 66:15;Gannes L Z et al., Comp Biochem Physiol Mol Integr Physiol 1998,119:725.

In the compounds of this invention any atom not specifically designatedas a particular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition. Also unlessotherwise stated, when a position is designated specifically as “D” or“deuterium”, the position is understood to have deuterium at anabundance that is at least 3340 times greater than the natural abundanceof deuterium, which is 0.015% (i.e., at least 50.1% incorporation ofdeuterium).

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance and the natural abundance of a specifiedisotope.

In other embodiments, a compound of this invention has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium), at least 5500 (82.5%deuterium incorporation), at least 6000 (90% deuterium incorporation),at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%deuterium incorporation), at least 6600 (99% deuterium incorporation),or at least 6633.3 (99.5% deuterium incorporation).

The term “isotopologue” refers to a species in which the chemicalstructure differs from a specific compound of this invention only in theisotopic composition thereof.

The term “compound,” when referring to a compound of this invention,refers to a collection of molecules having an identical chemicalstructure, except that there may be isotopic variation among theconstituent atoms of the molecules. Thus, it will be clear to those ofskill in the art that a compound represented by a particular chemicalstructure containing indicated deuterium atoms, will also contain lesseramounts of isotopologues having hydrogen atoms at one or more of thedesignated deuterium positions in that structure. The relative amount ofsuch isotopologues in a compound of this invention will depend upon anumber of factors including the isotopic purity of deuterated reagentsused to make the compound and the efficiency of incorporation ofdeuterium in the various synthesis steps used to prepare the compound.However, as set forth above the relative amount of such isotopologues intoto will be less than 49.9% of the compound. In other embodiments, therelative amount of such isotopologues in toto will be less than 47.5%,less than 40%, less than 32.5%, less than 25%, less than 17.5%, lessthan 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% ofthe compound.

The invention also provides salts of the compounds of the invention.

A salt of a compound of this invention is formed between an acid and abasic group of the compound, such as an amino functional group, or abase and an acidic group of the compound, such as a carboxyl functionalgroup. According to another embodiment, the compound is apharmaceutically acceptable acid addition salt.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent that is, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humans and other mammals withoutundue toxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. A “pharmaceuticallyacceptable salt” means any non-toxic salt that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention. A “pharmaceutically acceptable counterion”is an ionic portion of a salt that is not toxic when released from thesalt upon administration to a recipient.

Acids commonly employed to form pharmaceutically acceptable saltsinclude inorganic acids such as hydrogen bisulfide, hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, aswell as organic acids such as para-toluenesulfonic acid, salicylic acid,tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylicacid, fumaric acid, gluconic acid, glucuronic acid, formic acid,glutamic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonicacid, carbonic acid, succinic acid, citric acid, benzoic acid and aceticacid, as well as related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, sulfonate, xylene sulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycolate, maleate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and othersalts. In one embodiment, pharmaceutically acceptable acid additionsalts include those formed with mineral acids such as hydrochloric acidand hydrobromic acid, and especially those formed with organic acidssuch as maleic acid.

The compounds of the present invention, may contain an asymmetric carbonatom, for example, as the result of deuterium substitution or otherwise.As such, compounds of this invention can exist as either individualenantiomers, or mixtures of the two enantiomers. Accordingly, a compoundof the present invention will include both racemic mixtures, and alsoindividual respective stereoisomers that are substantially free fromanother possible stereoisomer. The term “substantially free of otherstereoisomers” as used herein means less than 25% of otherstereoisomers, in certain embodiments less than 10% of otherstereoisomers, in certain more specific embodiments less than 5% ofother stereoisomers and in certain yet more specific embodiments lessthan 2% of other stereoisomers. Methods of obtaining or synthesizing anindividual enantiomer for a given compound are well known in the art andmay be applied as practicable to final compounds or to starting materialor intermediates.

Unless otherwise indicated, when a disclosed compound is named ordepicted by a structure without specifying the stereochemistry and hasone or more chiral centers, it is understood to represent all possiblestereoisomers of the compound.

The term “stable compounds,” as used herein, refers to compounds whichpossess stability sufficient to allow for their manufacture and whichmaintain the integrity of the compound for a sufficient period of timeto be useful for the purposes detailed herein (e.g., formulation intotherapeutic products, intermediates for use in production of therapeuticcompounds, isolatable or storable intermediate compounds, treating adisease or condition responsive to therapeutic agents).

“D” and “d” both refer to deuterium. “Stereoisomer” refers to bothenantiomers and diastereomers. “Tert”, “^(t)”, and “t-” each refer totertiary. “US” refers to the United States of America.

Throughout this specification, a variable may be referred to generally(e.g., “each R”) or may be referred to specifically (e.g., R¹, R², R³,etc.). Unless otherwise indicated, when a variable is referred togenerally, it is meant to include all specific embodiments of thatparticular variable.

Therapeutic Compounds

The present invention in one embodiment provides a compound of FormulaI:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Z¹ is hydrogen or fluorine;    -   Z² is hydrogen, deuterium, or fluorine;    -   Z³ is deuterium;    -   Z⁴ is fluorine;    -   m is an integer from 0 to 10;    -   n is an integer from 0 to 2;

provided that:

-   -   the sum of m+n does not exceed 10; and    -   when both Z¹ and Z² are hydrogen, the sum of m+n is greater than        0.

In one embodiment, the invention provides a compound of Formula I,wherein:

-   -   m is 0, 2, 4, 6, 8, or 10; and    -   n is 0 or 2.

In another embodiment, the invention provides a compound of Formula I,wherein for each Z³ that is present, there is another Z³ present whichis attached to the same carbon. In an example of this embodiment, m is10 and Z² is hydrogen. In another example of this embodiment, m is 10and Z² is deuterium. In an example of this embodiment, m is 2, whereinthe carbon bearing the two deuterium atoms is the carbon in the4-position relative to the carbon attached to the C═O group; n is 0; andZ² is hydrogen. In another example of this embodiment, m is 2, whereinthe carbon bearing the two deuterium atoms is the carbon in the4-position relative to the carbon attached to the C═O group; n is 0; andZ² is deuterium. In an example of this embodiment, in is 6, wherein thethree carbons each bearing two deuterium atoms are the carbons in the3-position, in the 4-position, and in the 5-position relative to thecarbon attached to the C═O group; n is 0; and Z² is hydrogen. In anotherexample of this embodiment, m is 6, wherein the three carbons eachbearing two deuterium atoms are the carbons in the 3-position, in the4-position, and in the 5-position relative to the carbon attached to theC═O group; n is 0; and Z² is deuterium. In one aspect of the embodimentswherein m is 6, the isotopic enrichment factor is at least 6000 (90%deuterium incorporation), 6333.3 (95% deuterium incorporation), such asat least 6466.7 (97% deuterium incorporation).

In another embodiment, the invention provides a compound of Formula I,wherein for each Z⁴ that is present, there is another Z⁴ present whichis attached to the same carbon.

In another embodiment, the invention provides a compound of Formula I,wherein Z² is hydrogen.

In yet another embodiment, the compound is selected from any one of thefollowing compounds:

or a pharmaceutically acceptable salt thereof.

In one embodiment the compound of Formula I is a compound of Formula Ia:

where the designation (R) indicates that the designated carbon has the(R) stereochemistry;or a pharmaceutically acceptable salt thereof, wherein:

-   -   Z¹ is hydrogen or fluorine;    -   Z² is hydrogen, deuterium, or fluorine;    -   Z³ is deuterium;    -   Z⁴ is fluorine;    -   m is an integer from 0 to 10;    -   n is an integer from 0 to 2;

provided that:

-   -   the sum of m+n does not exceed 10; and    -   when both Z¹ and Z² are hydrogen, the sum of m+n is greater than        0.

In one embodiment of Formula Ia,

-   -   m is 0, 2, 4, 6, 8, or 10; and    -   n is 0 or 2.

In another embodiment of Formula Ia, for each Z³ that is present, thereis another Z³ present which is attached to the same carbon. In anexample of this embodiment, m is 10 and Z² is hydrogen. In anotherexample of this embodiment, m is 10 and Z² is deuterium. In an exampleof this embodiment, m is 2, wherein the carbon bearing the two deuteriumatoms is the carbon in the 4-position relative to the carbon attached tothe C═O group; n is 0; and Z² is hydrogen. In another example of thisembodiment, m is 2, wherein the carbon bearing the two deuterium atomsis the carbon in the 4-position relative to the carbon attached to theC═O group; n is 0; and Z² is deuterium. In an example of thisembodiment, m is 6, wherein the three carbons each bearing two deuteriumatoms are the carbons in the 3-position, in the 4-position, and in the5-position relative to the carbon attached to the C═O group; n is 0; andZ² is hydrogen. In another example of this embodiment, m is 6, whereinthe three carbons each bearing two deuterium atoms are the carbons inthe 3-position, in the 4-position, and in the 5-position relative to thecarbon attached to the C═O group; n is 0; and Z² is deuterium. In oneaspect of the embodiments wherein m is 6, the isotopic enrichment factoris at least 6000 (90% deuterium incorporation), 6333.3 (95% deuteriumincorporation), such as at least 6466.7 (97% deuterium incorporation).

In another embodiment of Formula Ia, for each Z⁴ that is present, thereis another Z⁴ present which is attached to the same carbon.

In another embodiment of Formula Ia, Z² is hydrogen.

In another embodiment of Formula Ia, Z² is deuterium.

In yet another embodiment, the compound of Formula Ia is selected fromany one of the following compounds:

or a pharmaceutically acceptable salt thereof.

In another set of embodiments, any atom not designated as deuterium inany of the embodiments set forth above is present at its naturalisotopic abundance.

The synthesis of compounds of Formula I and Formula Ia can be readilyachieved by synthetic chemists of ordinary skill. Relevant proceduresand intermediates are disclosed, for instance, in:

-   Kim, Joong Hyup; Lee, Yong; Park, Hokoon; Kim, Choong. Tetrahedron    (1998), 54(26):7395-7400.-   Shan, Yuhua; Lin, Furong; Yuan, Shunfu; Xu, Ping. Faming Zhuanli    Shenqing Gongkai Shuomingshu (2005), Chinese Patent Publication    CN100503582.-   El-Fayyoumy, Shaimaa; Mansour, Wafaa; Todd, Matthew H. Tetrahedron    Letters (2006), 47(8): 1287-1290.-   Todd, Matthew H.; Ndubaku, Chudi; Bartlett, Paul A. Journal of    Organic Chemistry (2002), 67(12):3985-3988.-   Kim, Joong Hyup; Lee, Yong; Kim, Choong. Heterocycles (1998),    48(11):2279-2285.-   Sergovskaya, N. L.; Chemyak, S. A.; Shekhter, O. V.; Tsizin, Yu. S.    Khimiya Geterotsiklicheskikh Soedinenii (1991), 8:1107-9.-   Yuste, Francisco; Pallas, Yadira; Barrios, Hector; Ortiz, Benjamin;    Sanchez-Obregon, Ruben. Journal of Heterocyclic Chemistry (1986),    23(1):189-90.-   Berkowitz, William F.; John, Thomas V. Journal of Organic Chemistry    (1984), 49(26):5269-71.-   Frehel, Daniel; Maffrand, Jean Pierre. Heterocycles (1983),    20(9):1731-5.

Such methods can be carried Out utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure.

Exemplary Synthesis

A convenient method for synthesizing compounds of Formula I is depictedin Scheme 1.

As described in the literature cited above and depicted in Scheme 1, asubstituted benzylamine I is acylated with 2-chloroacetyl chloride toafford chloride II. Chloride II is treated with 2,2-dimethoxyethanamineto provide acetal III. Formation of the HCl salt IV, followed bycyclization in the presence of concentrated sulfuric acid, affordstricycle V. Acylation with either acyl chlorides VI in the presence ofsodium carbonate or in the presence of triethylamine, or carboxylicacids VII in the presence of a coupling agent such as dicyclohexylcarbodiimide (DCC) provides compounds of Formula I. In Scheme 1, Z¹ isas defined for a compound of Formula I.

Schemes 2-4 depict the preparation of exemplary carboxylic acids VIIb,VIIe and VIId which are useful reagents for Scheme 1. Scheme 5 depicts aconvenient method for synthesizing intermediates of Formula Va for usein preparing compounds of Formula Ia.

As depicted in Scheme 2, commercially-availablecyclohexanecarboxylic-d11 acid VIIa is treated with HCl to affordexchanged carboxylic acid VIIb.

Alternatively, carboxylic acid VIIa may be converted to a methyl esterand treated with LDA (or NaOMe/MeOH), followed by ester hydrolysis toyield VIIb, in accordance with Scheme 2a.

As yet another alternative, commercially available ketone XIIa isconverted to aldehyde XIVa via a Wittig reaction. The aldehyde is thenoxidized with Oxone® reagent to yield VIIb, in accordance with Scheme2b.

Known cyclohexane-4,4-d2-carboxylic acid ethyl ester VIII [Journal ofthe Chemical Society, Perkin Transactions 1: Organic and Bio-OrganicChemistry (1995), (5), 527-35] is hydrolyzed to carboxylic acid VIIc, inaccordance with Scheme 3, by treatment with lithium hydroxide in aqueousTHF according to the method of Journal of Organic Chemistry, 58(23),6255-65; 1993.

VIII in Scheme 3 may be prepared as shown in Scheme 3a below:

As shown in Scheme 3a, commercially available IX is treated withp-toluenesulfonyl hydrazide (TsNHNH₂) to afford intermediate X, which istreated with sodium borodeuteride to provide VIII.

As shown in Scheme 4, commercially available IX is subjected tohydrogen/deuterium exchange via treatment with2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine and CDCl₃ to affordIXa. IXa is then treated with p-toluenesulfonyl hydrazide (TsNHNH₂) toafford intermediate Xa, which is treated with sodium borodeuteride toprovide VIIIa. Ester VIIIa is then hydrolyzed with LiOH to afford VIId.

Table 1 summarizes commercially available starting materials andreagents useful for the preparation of compounds depicted in Scheme 1.

TABLE 1 Compound Name

4-Fluorophenethylamine

2-Phenylethylamine

4,4-Difluorocyclohexylcarboxylic acid

Cyclohexanecarboxylic-d11 acid

Cyclohexanecarbonyl chloride

A convenient method for synthesizing intermediates of Formula Va for usein preparing compounds of Formula Ia is depicted in Scheme 5.

As shown in Scheme 5, resolving amine V (prepared as disclosed inScheme 1) via an intermediary salt IX provides R-enantiomer amine V(a)which may then be converted to the desired final products of Formula Iavia the methods indicated in Scheme 1 for the compounds of formula I.The chiral resolution of amine V is performed in a manner analogous tothat described online at:http://www.ourexperiment.org/racres_pzq/1309/Multigramscale_racemic_resolution_of_praziquanamine_with_DibenzoylLtartaric_acid_MW4913.html(accessed January 2011). In brief, V and (−)-dibenzoyl-L-tartaric acidare heated in aqueous iPrOH until a solution is formed. The solution isallowed to cool and the resulting salt precipitate is collected. Thecollected salt is recrystallized by heating in aqueous iPrOH until asolution is formed. The solution is allowed to cool and the resultingsalt precipitate is collected. The mother liquor may be cooled furtherto facilitate collection of additional crops of salt precipitate. Theisolated salt precipitate is suspended in water and the mixture is madebasic by addition of aqueous NaOH to pH 11. The resulting aqueoussolution is extracted with CH₂Cl₂ to afford the free base V(a).

The specific approaches and compounds shown above are not intended to belimiting. The chemical structures in the schemes herein depict variablesthat are hereby defined commensurately with chemical group definitions(moieties, atoms, etc.) of the corresponding position in the compoundformulae herein, whether identified by the same variable name (i.e., Z¹,Z², Z³, etc.) or not. The suitability of a chemical group in a compoundstructure for use in the synthesis of another compound is within theknowledge of one of ordinary skill in the art.

Additional methods of synthesizing compounds of Formula I or Ia andtheir synthetic precursors, including those within routes not explicitlyshown in schemes herein, are within the means of chemists of ordinaryskill in the art. Synthetic chemistry transformations and protectinggroup methodologies (protection and deprotection) useful in synthesizingthe applicable compounds are known in the art and include, for example,those described in Larock R, Comprehensive Organic Transformations, VCHPublishers (1989); Greene T W et al., Protective Groups in OrganicSynthesis, 3rd Ed., John Wiley and Sons (1999); Fieser L et al., Fieserand Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994);and Paquette L, ed., Encyclopedia of Reagents for Organic Synthesis,John Wiley and Sons (1995) and subsequent editions thereof.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds.

Compositions

The invention also provides pyrogen-free compositions comprising aneffective amount of a compound of Formula I or Ia (e.g., including anyof the formulae herein), or a pharmaceutically acceptable salt of saidcompound; and an acceptable carrier. Preferably, a composition of thisinvention is formulated for pharmaceutical use (“a pharmaceuticalcomposition”), wherein the carrier is a pharmaceutically acceptablecarrier. The carrier(s) are “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and, in thecase of a pharmaceutically acceptable carrier, not deleterious to therecipient thereof in an amount used in the medicament.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

If required, the solubility and bioavailability of the compounds of thepresent invention in pharmaceutical compositions may be enhanced bymethods well-known in the art. One method includes the use of lipidexcipients in the formulation. See “Oral Lipid-Based Formulations:Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs andthe Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare,2007; and “Role of Lipid Excipients in Modifying Oral and ParenteralDrug Delivery: Basic Principles and Biological Examples,” Kishor M.Wasan, ed. Wiley-Interscience, 2006.

Another known method of enhancing bioavailability is the use of anamorphous form of a compound of this invention optionally formulatedwith a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), orblock copolymers of ethylene oxide and propylene oxide. See U.S. Pat.No. 7,014,866; and United States patent publications 20060094744 and20060079502.

The pharmaceutical compositions of a compound of Formula I or Ia, or apharmaceutically acceptable salt thereof, include those suitable fororal, rectal, nasal, topical (including buccal and sublingual), vaginalor parenteral (including subcutaneous, intramuscular, intravenous andintradermal) administration. In certain embodiments, the compound of theformulae herein is administered transdermally (e.g., using a transdermalpatch or iontophoretic techniques). Other formulations may convenientlybe presented in unit dosage form, e.g., tablets, sustained releasecapsules, and in liposomes, and may be prepared by any methods wellknown in the art of pharmacy. See, for example, Remington: The Scienceand Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, Md.(20th ed. 2000).

Such preparative methods include the step of bringing into associationwith the molecule to be administered ingredients such as the carrierthat constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers, liposomes orfinely divided solid carriers, or both, and then, if necessary, shapingthe product.

In certain embodiments, the compound is administered orally.Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, sachets, or tabletseach containing a predetermined amount of the active ingredient; apowder or granules; a solution or a suspension in an aqueous liquid or anon-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oilliquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatincapsules can be useful for containing such suspensions, which maybeneficially increase the rate of compound absorption.

In the case of tablets for oral use, carriers that are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are administered orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozengescomprising the ingredients in a flavored basis, usually sucrose andacacia or tragacanth; and pastilles comprising the active ingredient inan inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampules and vials, and may be stored ina freeze dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents (such as, for example, Tween 80) andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of this invention may be administered inthe form of suppositories for rectal administration. These compositionscan be prepared by mixing a compound of this invention with a suitablenon-irritating excipient which is solid at room temperature but liquidat the rectal temperature and therefore will melt in the rectum torelease the active components. Such materials include, but are notlimited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art. See, e.g.: Rabinowitz J D and Zaffaroni A C, U.S. Pat. No.6,803,031, assigned to Alexza Molecular Delivery Corporation.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For topicalapplication topically to the skin, the pharmaceutical composition shouldbe formulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-transdermal patches andiontophoretic administration are also included in this invention.

Application of the subject therapeutics may be local, so as to beadministered at the site of interest. Various techniques can be used forproviding the subject compositions at the site of interest, such asinjection, use of catheters, trocars, projectiles, pluronic gel, stents,sustained drug release polymers or other device which provides forinternal access.

Thus, according to yet another embodiment, the compounds of thisinvention may be incorporated into compositions for coating animplantable medical device, such as prostheses, artificial valves,vascular grafts, stents, or catheters. Suitable coatings and the generalpreparation of coated implantable devices are known in the art and areexemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. Thecoatings are typically biocompatible polymeric materials such as ahydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethyleneglycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.The coatings may optionally be further covered by a suitable topcoat offluorosilicone, polysaccharides, polyethylene glycol, phospholipids orcombinations thereof to impart controlled release characteristics in thecomposition. Coatings for invasive devices are to be included within thedefinition of pharmaceutically acceptable carrier, adjuvant or vehicle,as those terms are used herein.

According to another embodiment, the invention provides a method ofcoating an implantable medical device comprising the step of contactingsaid device with the coating composition described above. It will beobvious to those skilled in the art that the coating of the device willoccur prior to implantation into a mammal.

According to another embodiment, the invention provides a method ofimpregnating an implantable drug release device comprising the step ofcontacting said drug release device with a compound or composition ofthis invention. Implantable drug release devices include, but are notlimited to, biodegradable polymer capsules or bullets, non-degradable,diffusible polymer capsules and biodegradable polymer wafers.

According to another embodiment, the invention provides an implantablemedical device coated with a compound or a composition comprising acompound of this invention, such that said compound is therapeuticallyactive.

According to another embodiment, the invention provides an implantabledrug release device impregnated with or containing a compound or acomposition comprising a compound of this invention, such that saidcompound is released from said device and is therapeutically active.

Where an organ or tissue is accessible because of removal from thesubject, such organ or tissue may be bathed in a medium containing acomposition of this invention, a composition of this invention may bepainted onto the organ, or a composition of this invention may beapplied in any other convenient way.

In another embodiment, a composition of this invention further comprisesa second therapeutic agent. The second therapeutic agent may be selectedfrom any compound or therapeutic agent known to have or thatdemonstrates advantageous properties when administered with a compoundhaving the same mechanism of action as Praziquantel. Such agents includethose indicated as being useful in combination with Praziquantel,including but not limited to, those described in WO 2005055973, WO2006061214, U.S. Pat. No. 4,303,659, U.S. Pat. No. 4,468,390, U.S. Pat.No. 4,447,414, WO 9505181, WO 9720567, WO 9806407, WO 2002094288, WO2004006906, and WO 2006120495.

Preferably, the second therapeutic agent is an agent useful in thetreatment or prevention of a disease or condition selected frominfections due to all species of schistosoma (e.g. Schistosoma mekongi,Schistosoma japonicum, Schistosoma mansoni and Schistosoma hematobium),and infections due to the liver flukes, Clonorchis sinensis/Opisthorchisviverrini; cysticercosis; neurocysticercosis (NCC); malaria; infectiondue to nematodes, sarcocystis, neosporosis or toxoplasmosis orisosporosis; animal infection or neoplasm of cerebrospinal tissuecharacterized by a risk of death; cancer; immune system dysfunctionincluding HIV infection; parasitic infection of farm and domesticanimals (pets) in the cases of cestodes, trematodoses, nematodoses andpests (ticks, mites and insects) invasions; parasitic diseases includingtoxoplasmosis, malaria, African trypanosomiasis, Chagas disease,leishmaniasis and schistosomiasis; helminthosis in domestic animals.

In one embodiment, the second therapeutic agent is selected fromalbendazole.

In another embodiment, the invention provides separate dosage forms of acompound of this invention and one or more of any of the above-describedsecond therapeutic agents, wherein the compound and second therapeuticagent are associated with one another. The term “associated with oneanother” as used herein means that the separate dosage forms arepackaged together or otherwise attached to one another such that it isreadily apparent that the separate dosage forms are intended to be soldand administered together (within less than 24 hours of one another,consecutively or simultaneously).

In the pharmaceutical compositions of the invention, the compound of thepresent invention is present in an effective amount. As used herein, theterm “effective amount” refers to an amount which, when administered ina proper dosing regimen, is sufficient to treat (therapeutically orprophylactically) the target disorder. For example, and effective amountis sufficient to reduce or ameliorate the severity, duration orprogression of the disorder being treated, prevent the advancement ofthe disorder being treated, cause the regression of the disorder beingtreated, or enhance or improve the prophylactic or therapeutic effect(s)of another therapy. In certain embodiments, the term “effective amount”refers to an amount which, when administered in a proper dosing regimen,is sufficient to therapeutically treat the target disorder

The interrelationship of dosages for animals and humans (based onmilligrams per meter squared of body surface) is described in Freireichet al., (1966) Cancer Chemother. Rep 50: 219. Body surface area may beapproximately determined from height and weight of the subject. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970,537.

In one embodiment, an effective amount of a compound of this inventioncan range from about 0.2 mg/kg of body weight to about 250 mg/kg of bodyweight per treatment. In more specific embodiments the range is fromabout 2 mg/kg to 125 mg/kg, or from about 4 mg/kg to 50 mg/kg, or mostspecifically from about 20 mg/kg to about 25 mg/kg or body weight pertreatment. Treatment typically is administered three times daily for oneday.

Effective doses will also vary, as recognized by those skilled in theart, depending on the diseases treated, the severity of the disease, theroute of administration, the sex, age and general health condition ofthe subject, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents and the judgment ofthe treating physician. For example, guidance for selecting an effectivedose can be determined by reference to the prescribing information forpraziquantel.

For pharmaceutical compositions that comprise a second therapeuticagent, an effective amount of the second therapeutic agent is betweenabout 20% and 100% of the dosage normally utilized in a monotherapyregime using just that agent. Preferably, an effective amount is betweenabout 70% and 100% of the normal monotherapeutic dose. The normalmonotherapeutic dosages of these second therapeutic agents are wellknown in the art. See, e.g., Wells et al., eds., PharmacotherapyHandbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDRPharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition,Tarascon Publishing, Loma Linda, Calif. (2000), each of which referencesare incorporated herein by reference in their entirety.

It is expected that some of the second therapeutic agents referencedabove will act synergistically with the compounds of this invention.When this occurs, it will allow the effective dosage of the secondtherapeutic agent and/or the compound of this invention to be reducedfrom that required in a monotherapy. This has the advantage ofminimizing toxic side effects of either the second therapeutic agent ofa compound of this invention, synergistic improvements in efficacy,improved ease of administration or use and/or reduced overall expense ofcompound preparation or formulation.

Methods of Treatment

In another embodiment, the invention provides a method of disruptingcell permeability to calcium ions in a parasitic cell, comprisingcontacting a cell with one or more compounds of Formula I or Ia herein.

According to another embodiment, the invention provides a method oftreating a disease or condition in a patient in need thereof that isbeneficially treated by praziquantel comprising the step ofadministering to said patient an effective amount of a compound or acomposition of this invention, or a pharmaceutically acceptable salt ofsaid compound. Such diseases and conditions are well known in the artand are disclosed in the following non-limited list of patents andpublished applications: U.S. Pat. No. 4,001,411, U.S. Pat. No.4,362,875, JP 51082298, U.S. Pat. No. 4,303,659, WO 9505181, WO 9720567,WO 2001089497, US 2003022879, WO 2004006906, WO 2004047842, and WO2007012180. Such diseases include, but are not limited to, infectionsdue to all species of schistosoma (e.g. Schistosoma mekongi, Schistosomajaponicum, Schistosoma mansoni and Schistosoma hematobium), andinfections due to the liver flukes, Clonorchis sinensis/Opisthorchisviverrini; cysticercosis; neurocysticercosis (NCC); malaria; infectiondue to nematodes, sarcocystis, neosporosis or toxoplasmosis orisosporosis; animal infection or neoplasm of cerebrospinal tissuecharacterized by a risk of death; cancer; immune system dysfunctionincluding HIV infection; parasitic infection of farm and domesticanimals (pets) in the cases of cestodes, trematodoses, nematodoses andpests (ticks, mites and insects) invasions; parasitic diseases includingtoxoplasmosis, malaria, African trypanosomiasis, Chagas disease,leishmaniasis and schistosomiasis; and helminthosis in domestic animals.Such indications also include fascioliasis, paragonimiasis, tapewormsand cestodes, including: Echinococcosis; Cysticercosis; and intestinaltapeworms.

In one particular embodiment, the method of this invention is used totreat a disease or condition in a patient in need thereof selected frominfections due to all species of schistosoma (e.g. Schistosoma mekongi,Schistosoma japonicum, Schistosoma mansoni and Schistosoma hematobium),and infections due to the liver flukes, Clonorchis sinensis/Opisthorchisviverrini; cysticercosis; neurocysticercosis (NCC); and malaria.

In another particular embodiment, the method of this invention is usedto treat a disease or condition in a patient in need thereof selectedfrom infections due to all species of schistosoma (e.g. Schistosomamekongi, Schistosoma japonicum, Schistosoma mansoni and Schistosomahematobium), and infections due to the liver flukes, Clonorchissinensis/Opisthorchis viverrini.

In one embodiment, the method is a method for the treatment of a diseaseor condition selected from indications that may be treated withanthelmintics, antischistosomals and antitrematodes. In one embodiment,the method is a method for the treatment of fascioliasis,paragonimiasis, tapeworms and cestodes, including: Echinococcosis;Cysticercosis; and intestinal tapeworms. In one embodiment, the methodis a method for (a) the removal of tapeworm in dogs; (b) in combinationwith pyrantel pamoate and febantel, for the removal of hookworms,roundworms, and whipworms in dogs; (c) the removal of tapeworm in cats;(d) in combination with pyrantel pamoate, the removal of hookworms androundworms in cats; (e) the removal of tapeworms in ferrets, birds,chinchillas, mice, rats, hamsters, gerbils, or guinea pigs; (f) theremoval of tapeworms and flukes in reptiles.

Methods delineated herein also include those wherein the patient isidentified as in need of a particular stated treatment. Identifying apatient in need of such treatment can be in the judgment of a patient ora health care professional and can be subjective (e.g. opinion) orobjective (e.g. measurable by a test or diagnostic method).

In another embodiment, any of the above methods of treatment comprisesthe further step of co-administering to said patient one or more secondtherapeutic agents. The choice of second therapeutic agent may be madefrom any second therapeutic agent known to be useful forco-administration with praziquantel. The choice of second therapeuticagent is also dependent upon the particular disease or condition to betreated. Examples of second therapeutic agents that may be employed inthe methods of this invention are those set forth above for use incombination compositions comprising a compound of this invention, or apharmaceutically acceptable salt thereof, and a second therapeuticagent.

In particular, the combination therapies of this invention includeco-administering a compound of Formula I or Ia, or a pharmaceuticallyacceptable salt thereof, and a second therapeutic agent for treatment ofthe following conditions (with the particular second therapeutic agentindicated in parentheses following the indication): neurocysticercosis(albendazole), and malaria (albendazole).

The term “co-administered” as used herein means that the secondtherapeutic agent may be administered together with a compound of thisinvention as part of a single dosage form (such as a composition of thisinvention comprising a compound of Formula I or Ia, or apharmaceutically acceptable salt thereof, and a second therapeutic agentas described above) or as separate, multiple dosage forms.Alternatively, the additional agent may be administered prior to,consecutively with, or following the administration of a compound ofthis invention. In such combination therapy treatment, both thecompounds of this invention and the second therapeutic agent(s) areadministered by conventional methods. The administration of acomposition of this invention, comprising both a compound of Formula Ior Ia, or a pharmaceutically acceptable salt thereof; and a secondtherapeutic agent, to a patient does not preclude the separateadministration of that same therapeutic agent, any other secondtherapeutic agent or any compound of this invention to said patient atanother time during a course of treatment.

Effective amounts of these second therapeutic agents are well known tothose skilled in the art and guidance for dosing may be found in patentsand published patent applications referenced herein, as well as in Wellset al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange,Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000),and other medical texts. However, it is well within the skilledartisan's purview to determine the second therapeutic agent's optimaleffective-amount range.

In one embodiment, where a second therapeutic agent is administered to asubject, the effective amount of the compound of this invention is lessthan its effective amount would be where the second therapeutic agent isnot administered. In another embodiment, the effective amount of thesecond therapeutic agent is less than its effective amount would bewhere the compound of this invention is not administered. In this way,undesired side effects associated with high doses of either agent may beminimized. Other potential advantages (including without limitationimproved dosing regimens and/or reduced drug cost) will be apparent tothose of skill in the art.

In yet another aspect, the invention provides a compound of Formula I orIa, or a pharmaceutically acceptable salt thereof, alone or togetherwith one or more of the above-described second therapeutic agents foruse in the treatment or prevention in a patient of a disease, disorderor symptom thereof delineated herein.

EXAMPLES Example 1 Synthesis of2,2,3,3,4,4,5,5,6,6-d10-Cyclohexanecarboxylic acid (VIIb)

Intermediate VIIb was prepared as outlined in Scheme 6 below.

Step 1. Methyl-cyclohexane-d11-carboxylate (XIa)

A solution of commercially available cyclohexane-d11-carboxylic acidVIIa (1 g, 6.67 mmol, 1 equiv, CDN, 98 atom % D) in toluene (10 mL) wastreated with SOCl₂ (0.5 mL, 6.8 mmol, 1.05 equiv). The mixture washeated at reflux for 2 hours and cooled to room temperature. Methanol (5mL) was added, and the mixture was stirred for another 1 hour. Thesolvent was then evaporated yielding XIa (1 g, 91%) as a colorless oil.

Step 2. Methyl-2,2,3,3,4,4,5,5,6,6-d10-cyclohexanecarboxylate (XIb)

XIa (1 g, 6.1 mmol, 1 equiv) was dissolved in THF (10 mL) and cooled to−78° C. LDA (12 mL, 1 M in THF, 12 mmol, 2 equiv) was added drop-wise.The mixture was stirred for 4 hours at −78° C. then quenched withsaturated NH₄Cl (10 mL) and warmed to room temperature. The mixture wasextracted with ethyl acetate (3×10 mL). The combined organic layers weredried over Na₂SO₄, filtered, and evaporated. The residue was resubjectedto the above D/H exchange conditions. After the second exchange cycle,1.1 g of crude XIb was obtained.

Step 3. 2,2,3,3,4,4,5,5,6,6-d10-Cyclohexanecarboxylic acid (VIIb)

A solution of XIb (1 g, 6.1 mmol, 1 equiv, assumes 100% yield inprevious step) in THF (10 mL) was treated with HCl (10 mL, 1M in water,1.6 equiv). The reaction was heated at reflux overnight, then cooled toroom temperature and concentrated to provide crude VIIb (0.8 g, 88.9%)which was used without purification.

Example 1a Synthesis of 2,2,3,3,4,4,5,5,6,6-d10-Cyclohexanecarboxylicacid (VIIb)

Intermediate VIIb was prepared as outlined in Scheme 6a below.

Step 1. 2,2,3,3,4,4,5,5,6,6-d10-cyclohexanecarbaldehyde (XIVa)

(Methoxymethyl)triphenylphosphonium chloride (13.48 g, 39.2 mmol, 1.1equiv) was suspended in anhydrous THF (200 mL) and cooled to −78° C. Asolution of 1.0 M lithium bis(trimethylsilyl)amide in THF (39.2 mL, 39.2mmol, 1.1 equiv) was added drop-wise over 0.5 hours. The reactionmixture was then stirred at −78° C. for another 2 hours followed by theaddition of a solution of d10-cyclohexanone XIIa (3.8 g, 35.6 mmol, 1.0equiv, CDN, 99 atom % D) in anhydrous THF (15 mL). The reaction wasslowly warmed to room temperature and stirred overnight. GC-MS analysisconfirmed conversion to XIIIa. Next, 2N HCl (60 mL) was added and thereaction was stirred for 1 hour, at which time GC-MS showed the completeconversion to XIVa. The reaction mixture was extracted with diethylether (100 mL×4). The organic layer was dried with Na₂SO₄, filtered, andconcentrated under reduced pressure at 0-5° C. to give crude XIVa (14 g)as a yellow oil which was used directly in the next step.

Step 2. Cyclohexane-2,2,3,3,4,4,5,5,6,6-d10-carboxylic acid (VIIb).

A portion of crude XIVa (6 g, 9.3 mmol, assumes 100% yield in theprevious step, 1 equiv) was dissolved in DMF (50 mL) followed by theaddition of Oxone® reagent (17.8 g, 27.9 mmol, 3.0 equiv). The mixturewas stirred at room temperature overnight followed by the addition ofaqueous 1N HCl (100 mL). The mixture was extracted with CH₂Cl₂ (100mL×5). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The residue was purified via silica gel chromatography(0%-50% ethyl acetate in heptanes) to give VIIb, a colorless oil whichsolidified upon standing (0.49 g, 39% yield over 2 steps).

Example 2 Synthesis of 4,4-d2-Cyclohexanecarboxylic acid (VIIc)

Intermediate VIIc was prepared as outlined in Scheme 7 below.

Step 1. Ethyl-4,4-d2-cyclohexanecarboxylate (VIII).

Commercially available ethyl 4-oxocyclohexanecarboxylate IX (4.6 g, 27mmol, 1.0 equiv) was dissolved in methanol-d1 (50 mL, Cambridge IsotopeLabs, 99 atom % D) followed by the addition of p-toluenesulfonylhydrazide (5 g, 27 mmol, 1.0 equiv). The mixture was stirred at roomtemperature for 1 h, and sodium borodeuteride (3.4 g, 81 mmol, 3.0equiv, Cambridge Isotope Labs, 99 atom % D) was added to the reactionmixture. The mixture was stirred for 30 minutes at reflux, cooled to 0°C., quenched with an aqueous solution of 2N HCl (50 mL), and extractedwith EtOAc (3×100 mL). The organic layer was washed with saturatedaqueous NaHCO₃, water, brine, dried with Na₂SO₄, filtered, andconcentrated to give VIII as a light yellow oil (3.6 g, 84% yield).

Step 2. 4,4-d2-Cyclohexanecarboxylic acid (VIIc)

VIII (3.5 g, 22 mmol, 1.0 equiv) was dissolved in a solution ofTHF/water (1:1) (50 mL) followed by the addition of LiOH (2.1 g, 88mmol, 4 equiv). The mixture was stirred for 3 hours at 65° C., cooled toroom temperature, and acidified with aqueous 2N HCl to adjust the pH to3. The mixture was extracted with CH₂Cl₂ (3×100 mL). The combinedorganic layers were dried with Na₂SO₄, filtered, and concentrated togive VIIc as an off-white solid (1.6 g, 56% yield).

Example 3 Synthesis of 3,3,4,4,5,5-d6-Cyclohexanecarboxylic acid (VIId)

Intermediate VIId was prepared as outlined in Scheme 8 below.

Step 1. Ethyl-3,3,5,5-d4-4-Oxocyclohexanecarboxylate (IXa)

Commercially available ethyl 4-oxocyclohexanecarboxylate IX (1.7 g, 10mmol, 1.0 equiv) was dissolved in chloroform-d1 (25 mL, CambridgeIsotope Labs, 99.9 atom % D) followed by the addition of2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (140 mg, 1.0 mmol,0.1 equiv). The reaction was stirred at room temperature for 1 h,diluted with CH₂Cl₂ (25 mL), and washed with 1 N HCl (1×100 mL). Theorganic layer was dried with Na₂SO₄, filtered, and concentrated. Theresulting oil was purified by silica gel chromatography eluting with10-40% ethyl acetate in heptanes. Proton NMR of the recovered productindicated that ˜20% proton remained. A second exchange cycle wascompleted yielding IXa as a colorless liquid (1.3 g, 74% yield).

Step 2. Ethyl-3,3,4,4,5,5-d6-Cyclohexanecarboxylate (VIIIa)

Compound IXa (1.1 g, 6.3 mmol, 1.0 equiv) was dissolved in methanol-d1(35 mL, Cambridge Isotope Labs, 99 atom % D) followed by the addition ofp-toluenesulfonyl hydrazide (1.2 g, 6.3 mmol, 1.0 equiv). The mixturewas stirred at room temperature for 1 h, and sodium borodeuteride (0.79g, 18.9 mmol, 3.0 equiv, Cambridge Isotope Labs, 99 atom % D) was addedto the reaction mixture. The mixture was stirred for 1 h at roomtemperature, cooled to 0° C., quenched with an aqueous solution of 1NHCl (10 mL), and extracted with EtOAc (3×100 mL). The combined organiclayer was washed with saturated aqueous NaHCO₃, water, brine, dried withNa₂SO₄, filtered, and concentrated to give VIIIa as an off-whitesemi-solid (1.7 g, crude, 70% pure (¹H NMR), used as such).

Step 3. 3,3,4,4,5,5-d6-Cyclohexanecarboxylic acid (VIId)

Crude compound VIIIa (1.7 g, 6.3 mmol, 1.0 equiv, assumes 100% yield inprevious step) was dissolved in a solution of THF/water (1:1) (30 mL)followed by the addition of LiOH (0.60 g, 25.2 mmol, 4 equiv). Themixture was stirred overnight at room temperature, diluted with water(50 mL), and extracted with MTBE (2×50 mL). The aqueous layer was cooledto 0° C. and acidified with aqueous 1N HCl to adjust the pH to 3. Themixture was extracted with CH₂Cl₂ (4×50 mL). The combined organic layerswere dried with Na₂SO₄, filtered, and concentrated. The crude materialwas purified via silica gel chromatography eluting with 10-50% ethylacetate in heptanes to give VIId as a colorless oil which solidifiedupon standing (0.55 g, 65% yield over 2 steps).

Example 4 Synthesis of(R)-2,3,6,7-Tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one (V(a1))

Intermediate V(a1) was prepared as outlined in Scheme 9 below.

(R)-2,3,6,7-Tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one (V(a1))

This resolution was conducted in a manner similar to that described inthe literature and on an open-source scientific website with thefollowing URL:http://www.ourexperiment.org/racres_pzq/1309/Multigramscale_racemic_resolution_of_praziquanamine_with_DibenzoylLtartaric_acid_MW4913.html.Thus, V(aa) (4 g, 19.8 mmol, 1.0 equiv, prepared as described in Kim, J.H.; et al. Tetrahedron 1998, 54(26), 7395-7400) was dissolved in amixture of iPrOH (190 mL) and water (38 mL) followed by the addition of(−)-dibenzoyl-L-tartaric acid (7.1 g, 19.8 mmol, 1.0 equiv). The mixturewas heated at 50-60° C. for 30 min. The mixture was then cooled in awater bath to room temperature and stirred for 4 hours. The solid wasfiltered and dried to give salt IX (3.8 g) as a white solid.Intermediate IX (3.8 g) was added to water (38 mL) and the stirredsuspension was carefully adjusted to pH 10-11 by adding an aqueoussolution of 2N NaOH. When the salt was completely dissolved the solutionwas extracted with CH₂Cl₂ (4×25 mL). The organic layer was washed withbrine, dried over sodium sulfate and concentrated to give V(a1) as alight yellow solid (1.9 g, yield 47.5%, 94% ee). The resolutionprocedure was repeated a second time to give V(a1) as a light yellowsolid (1.7 g, recovery rate 89%, 99% ee).

Example 5 Synthesis of(R)-2-(Cyclohexane-d11-carbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one(102a)

Compound 102a was prepared as outlined in Scheme 10 below.

(R)-2-(Cyclohexane-d11-carbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one(102a)

Commercially available cyclohexane-d11-carboxylic acid VIIa (240 mg,1.73 mmol, 1.0 equiv, CDN, 98 atom % D) and V(a1) (350 mg, 1.73 mmol,1.0 equiv) were dissolved in anhydrous DMF (20 mL) followed by theaddition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(EDC, 400 mg, 2.1 mmol, 1.2 equiv) and hydroxybenzotriazole (HOBt, 280mg, 2.1 mmol, 1.2 equiv). The mixture was stirred at room temperatureovernight and diluted with ethyl acetate (100 mL). The mixture waswashed with aqueous saturated NH₄Cl, aqueous saturated NaHCO₃, brine,dried with Na₂SO₄, filtered, and concentrated. The resulting residue waspurified via silica gel chromatography eluting with 0-30% ethyl acetatein heptanes to give 102a as a white solid (400 mg, 71% yield). ¹H NMR(300 MHz, CDCl₃) δ ppm: 7.28-7.17 (m, 4H), 5.16 (d, 2H), 4.80 (m, 2H),4.47 (d, 1H), 4.07 (d, 1H), 3.00-2.79 (M, 4H), (minor rotational isomeralso present); LCMS m/z=324 [M+H]⁺.

Example 6 Synthesis of(R)-2-(4,4-d2-Cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one(101a)

Compound 101a was prepared in a manner analogous to that outlined inScheme 10 above.

(R)-2-(4,4-d2-Cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one(101a)

Compound 101a was prepared in an analogous fashion to Compound 102a fromV(a1) and VIIc. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.28-7.17 (m, 4H), 5.16(d, 2H), 4.80 (m, 2H), 4.47 (d, 1H), 4.07 (d, 1H), 3.00-2.79 (M, 4H),2.51 (t, 1H), 1.79 (t, 4H), 1.58 (t, 2H), 1.28 (t, 2H), (minorrotational isomer also present); LCMS m/z=315 [M+H]⁺.

Example 7 Synthesis of(R)-2-(2,2,3,3,4,4,5,5,6,6-d10-Cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one(103a)

Compound 103a was prepared in a manner analogous to that outlined inScheme 10 above.

(R)-2-(2,2,3,3,4,4,5,5,6,6-d10-Cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one(103a)

Compound 103a was prepared in an analogous fashion to Compound 102a fromV(a1) and VIIb. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.28-7.17 (m, 4H), 5.16(d, 2H), 4.80 (m, 2H), 4.47 (d, 1H), 4.07 (d, 1H), 3.00-2.79 (M, 4H),2.44 (s, 1H), (minor rotational isomer also present); LCMS m/z=323[M+H]⁺.

Example 8 Synthesis of(R)-2-(3,3,4,4,5,5-d6-Cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one(109a)

Compound 109a was prepared in a manner analogous to that outlined inScheme 10 above.

(R)-2-(3,3,4,4,5,5-d6-Cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one(109a)

Compound 109a was prepared in an analogous fashion to Compound 102a fromV(aa) and VIId. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.28-7.19 (m, 4H), 5.16(d, 1H), 4.81 (m, 2H), 4.47 (d, 1H), 4.08 (d, 1H), 2.99-2.76 (M, 4H),2.46 (t, 1H), 1.73 (m, 2H), 1.52 (m, 2H) (minor rotational isomer alsopresent); LCMS m/z=319 [M+H]⁺.

Example 9 Synthesis of2-(Cyclohexane-d11-carbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one(102)

Compound 102 was prepared as outlined in Scheme 11 below.

2-(Cyclohexane-d11-carbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one(Compound 102)

Commercially available cyclohexane-d11-carboxylic acid VIIa (300 mg,2.16 mmol, 1.0 equiv, CDN, 98 atom % D) was dissolved in anhydroustoluene (10 mL) followed by the addition of thionyl chloride (0.6 mL,8.64 mmol, 4.0 equiv). The mixture was stirred at 60° C. for 1 hour andthen concentrated under reduced pressure. The excess thionyl chloridewas chased with toluene (2×10 mL). The resulting residue was dissolvedin CH₂Cl₂ (20 mL) and cooled to 0° C. followed by the addition of amixture of V(aa) (440 mg, 2.16 mmol, 1.0 equiv; prepared as described inKim, J. H.; et al. Tetrahedron 1998, 54(26), 7395-7400) andtriethylamine (0.6 mL, 4.3 mmol, 2.0 equiv) in CH₂Cl₂ (10 mL). Themixture was stirred at room temperature for 3 hours and quenched withaqueous saturated NaHCO₃ (20 mL). The organic layer was washed withbrine, dried with Na₂SO₄, filtered, and concentrated. The resultingresidue was purified via silica gel chromatography eluting with 0-30%ethyl acetate in heptanes, and then recrystallized from ethylacetate/heptanes (1:3) to give 102 as a white solid (300 mg, 44% yield).¹H NMR (300 MHz, CDCl₃) δ ppm: 7.28-7.17 (m, 4H), 5.16 (d, 1H), 4.80 (m,2H), 4.47 (d, 1H), 4.07 (d, 1H), 3.00-2.79 (M, 4H), (minor rotationalisomer also present); LCMS m/z=324 [M+H]⁺.

Example 10 Synthesis of2-(4,4-d2-Cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one(101)

Compound 101 was prepared in a manner analogous to that outlined inScheme 10 above.

2-(Cyclohexane-4,4-d2-carbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one(Compound 101)

Compound 101 was prepared in an analogous fashion to Compound 102a fromV(aa) and Wk. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.28-7.17 (m, 4H), 5.16 (d,1H), 4.80 (m, 2H), 4.47 (d, 1H), 4.07 (d, 1H), 3.00-2.79 (M, 4H), 2.51(t, 1H), 1.79 (t, 4H), 1.58 (t, 2H), 1.28 (t, 2H), (minor rotationalisomer also present); LCMS m/z=315 [M+H]⁺.

Example 11 Synthesis of2-(2,2,3,3,4,4,5,5,6,6-d10-Cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one(103)

Compound 103 was prepared in a manner analogous to that outlined inScheme 10 above.

2-(Cyclohexane-2,2,3,3,4,4,5,5,6,6-d10-carbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one(Compound 103)

Compound 103 was prepared in an analogous fashion to Compound 102a fromV(aa) and VIIb. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.28-7.17 (m, 4H), 5.16(d, 1H), 4.80 (m, 2H), 4.47 (d, 1H), 4.07 (d, 1H), 3.00-2.79 (M, 4H),2.44 (s, 1H), (minor rotational isomer also present); LCMS m/z=323[M+H]⁺.

Example 12 Synthesis of2-(3,3,4,4,5,5-d6-Cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one(109)

Compound 109 was prepared in a manner analogous to that outlined inScheme 10 above.

2-(Cyclohexane-3,3,4,4,5,5,-d6-carbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one(Compound 109)

Compound 109 was prepared in an analogous fashion to Compound 102a fromV(aa) and VIId. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.28-7.19 (m, 4H), 5.16(d, 1H), 4.81 (m, 2H), 4.47 (d, 1H), 4.07 (d, 1H), 3.00-2.79 (M, 4H),2.46 (t, 1H), 1.72 (m, 2H), 1.52 (m, 2H) (minor rotational isomer alsopresent); LCMS m/z=319 [M+H]⁺.

Evaluation of Metabolic Stability

Certain in vitro liver metabolism studies have been described previouslyin the following references, each of which is incorporated herein intheir entirety: Obach, RS, Drug Metab Disp, 1999, 27:1350; Houston, J Bet al., Drug Metab Rev, 1997, 29:891; Houston, JB, Biochem Pharmacol,1994, 47:1469; Iwatsubo, T et al., Pharmacol Ther, 1997, 73:147; andLave, T, et al., Pharm Res, 1997, 14:152. Microsomal Assay: Human livermicrosomes (20 mg/mL) are obtained from Xenotech, LLC (Lenexa, Kans.).β-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH),magnesium chloride (MgCl₂), and dimethyl sulfoxide (DMSO) are purchasedfrom Sigma-Aldrich.

Determination of Metabolic Stability:

7.5 mM stock solutions of test compounds were prepared in DMSO. The 7.5mM stock solutions were diluted to 50 in acetonitrile (ACN). The 20mg/mL human liver microsomes were diluted to 0.625 mg/mL in 0.1 Mpotassium phosphate buffer, pH 7.4, containing 3 mM MgCl₂. The dilutedmicrosomes were added to wells of a 96-well deep-well polypropyleneplate in triplicate. A 10 μL aliquot of the 50 μM test compound wasadded to the microsomes and the mixture was pre-warmed for 10 minutes.Reactions were initiated by addition of pre-warmed NADPH solution. Thefinal reaction volume was 0.5 mL and contained 0.5 mg/mL human livermicrosomes, 1.0 μM test compound, and 2 mM NADPH in 0.1 M potassiumphosphate buffer, pH 7.4, and 3 mM MgCl₂. The reaction mixtures wereincubated at 37° C., and 50 μL aliquots were removed at 0, 5, 10, 20,and 30 minutes and added to shallow-well 96-well plates which contained50 μL of ice-cold ACN with internal standard to stop the reactions. Theplates were stored at 4° C. for 20 minutes after which 100 μL of waterwas added to the wells of the plate before centrifugation to pelletprecipitated proteins. Supernatants were transferred to another 96-wellplate and analyzed for amounts of parent remaining by LC-MS/MS using anApplied Bio-systems API 4000 mass spectrometer. The same procedure wasfollowed for praziquantel and the positive control, 7-ethoxycoumarin (1μM). Testing was done in triplicate.

Data Analysis:

The in vitro half-lives (t_(1/2)s) for test compounds were calculatedfrom the slopes of the linear regression of % parent remaining (ln) vsincubation time relationship:

in vitro t _(1/2)=0.693/k, where k=−[slope of linear regression of %parent remaining (ln) vs incubation time]

The results of the HLM assays are shown in Tables 1-3. Table 1 shows theresults of the t½ values measured in HLM for praziquantel and forCompounds 101 and 102. Table 2 shows the results of the t½ valuesmeasured in HLM for praziquantel for Compounds 101, 109, 103 and 102.Table 3 shows the results of the t½ values measured in HLM forpraziquantel and (R)-praziquantel and for Compounds 101(a), 109(a),103(a) and 102(a). For each table, the t½ values in each of four runs,as well as the average values, are provided together with the percentageincrease in the t½ value relative to a non-deuterated compound(praziquantel and/or (R)-praziquantel.

TABLE 1 Half-life (t½) values measured in Human Liver Microsomes t_(1/2)(min) AVE ± SD and % increase in AVE Run Run Run Run relative toCompound No. 1 No. 2 No. 3 No. 4 praziquantel Praziquantel 36.2 37.337.3 44.7 38.9 ± 3.9 101 47.4 43.6 43.1 52.7 46.7 ± 4.4 20% 102 56.455.4 44.8 66.2 55.7 ± 8.7 43%

TABLE 2 Half-life (t½) values measured in Human Liver Microsomes t_(1/2)(min) AVE ± SD and % increase in AVE Run Run Run Run relative toCompound No. 5 No. 6 No. 7 No. 8 praziquantel Praziquantel 41.2 43.830.6 36.9 38.1 ± 5.8 101 56.7 53.9 38.2 60.1 52.2 ± 9.7 37% 109 55.753.5 46.4 51.2 52.2 ± 4.6 37% 103 65.1 51.6 60.6 69.3 61.7 ± 7.6 62% 10254.8 50.6 44.9 52.4 50.7 ± 4.2 33%

TABLE 3 Half-life (t½) values measured in Human Liver Microsomes AVE ±SD and % increase in AVE a) relative to Run Run praziquantel, andCompound Run No. Run No. No. No. b) relative to (R)- ID 9 10 11 12praziquantel Praziquantel 29.5 31.5 35.1 30.5 31.7 ± 2.5 (R) 37.5 36.440.0 41.8 38.2 ± 2.5 Praziquantel 101(a) 48.9 46.7 56.3 45.8 49.4 ± 4.8a) 56% b) 29% 109(a) 39.5 38.7 43.2 55.4 44.2 ± 7.7 a) 40% b) 16% 103(a)52.7 41.8 50.0 55.5 50.0 ± 5.9 a) 58% b) 31% 102(a) 57.4 53.6 50.1 46.051.8 ± 4.9 a) 64% b) 36%

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the illustrativeexamples, make and utilize the compounds of Formula I or Ia and practicethe claimed methods. It should be understood that the foregoingdiscussion and examples merely present a detailed description of certainpreferred embodiments. It will be apparent to those of ordinary skill inthe art that various modifications and equivalents can be made withoutdeparting from the spirit and scope of the invention. All the patents,journal articles and other documents discussed or cited above are hereinincorporated by reference.

1. A compound of Formula Ia:

where the designation (R) indicates that the designated carbon has the(R) stereochemistry; or a pharmaceutically acceptable salt thereof,wherein: Z¹ is hydrogen or fluorine; Z² is hydrogen, deuterium, orfluorine; Z³ is deuterium; Z⁴ is fluorine; m is an integer from 0 to 10;n is an integer from 0 to 2; provided that: the sum of m+n does notexceed 10; and when both Z¹ and Z² are hydrogen, the sum of m+n isgreater than
 0. 2. The compound of claim 1, wherein m is 0, 2, 4, 6, 8,or 10; and n is 0 or
 2. 3. The compound of claim 2, wherein for each Z³that is present, there is another Z³ present which is attached to thesame carbon.
 4. The compound of claim 3, wherein m is 10 and Z² ishydrogen.
 5. The compound of claim 3, wherein m is 10 and Z² isdeuterium.
 6. The compound of claim 3, wherein m is 2, wherein thecarbon bearing the two deuterium atoms is the carbon in the 4-positionrelative to the carbon attached to the C═O group; n is 0; and Z² ishydrogen.
 7. The compound of claim 3, wherein m is 2, wherein the carbonbearing the two deuterium atoms is the carbon in the 4-position relativeto the carbon attached to the C═O group; n is 0; and Z² is deuterium. 8.The compound of claim 3, wherein m is 6, wherein the three carbons eachbearing two deuterium atoms are the carbons in the 3-position, in the4-position, and in the 5-position relative to the carbon attached to theC═O group; n is 0; and Z² is hydrogen.
 9. The compound of claim 3,wherein m is 6, wherein the three carbons each bearing two deuteriumatoms are the carbons in the 3-position, in the 4-position, and in the5-position relative to the carbon attached to the C═O group; n is 0; andZ² is deuterium.
 10. The compound of claim 1, wherein Z² is hydrogen.11. The compound of claim 1, wherein Z² is deuterium.
 12. The compoundof claim 1, wherein the compound is selected from any one of thefollowing compounds:

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim1, wherein the compound is selected from any one of the followingcompounds:

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim1, wherein any atom not designated as deuterium is present in itsnatural isotopic abundance.
 15. A pharmaceutical composition comprisinga compound of claim 1 or a pharmaceutically acceptable salt of saidcompound; and a pharmaceutically acceptable carrier.
 16. The compositionof claim 15 further comprising a second therapeutic agent which is usedto treat malaria or infections due to schistosoma or liver flukes. 17.The composition of claim 16 wherein the second therapeutic agent isalbendazole.
 18. A method of disrupting cell permeability to calciumions in a parasitic cell, comprising contacting a cell with a compoundof claim
 1. 19. A method of treating a disease or condition selectedfrom schistosoma infections, liver fluke infections, Clonorchissinensis/Opisthorchis viverrini; cysticercosis; neurocysticercosis(NCC); and malaria, in a patient in need thereof comprising the step ofadministering to said patient an effective amount of a compound of claim1, or a pharmaceutically acceptable salt of said compound.
 20. A methodof treating infections due to nematodes, sarcocystis, neosporosis,toxoplasmosis, isosporosis; parasitic infection of farm and domesticanimals selected from cestodes, trematodoses, nematodoses and pestsinvasions; toxoplasmosis, African trypanosomiasis, Chagas disease,leishmaniasis, schistosomiasis, helminthosis, fascioliasis,paragonimiasis, and tapeworms in a mammal in need thereof comprising thestep of administering to said mammal an effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt of said compound.